Foamable suspension gel

ABSTRACT

The present subject matter provides foamable suspension gels that foam after release from a container. The foamable suspension gels contain at least one pharmaceutically active agent that is sparingly soluble to insoluble in water, a second pharmaceutically active agent, and optionally a third active agent.

This is a Continuation application filed under 35 U.S.C. §120, as acontinuation of Ser. No. 11/730,011, filed on Mar. 29, 2007, now U.S.Pat. No. 8,158,109 an application claiming the benefit under 35 U.S.C.§119(e) of U.S. Provisional Application No. 61/744,082, filed on Mar.31, 2006, the content of each of which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present subject matter relates to topical delivery of at least oneactive agent that is sparingly soluble to insoluble in water,particularly benzoyl peroxide, in an aqueous, foamable suspension gel.

BACKGROUND OF THE INVENTION

There are many challenges in the topical application of pharmaceuticallyactive agents. One major objective is to achieve percutaneous deliveryof the active agent to the site of treatment. The composition shouldalso have desirable cosmetic characteristics. Application should be easyand should not leave a noticeable residue on the surface of the skin.Moreover, the composition should not cause irritation, discomfort, orinconvenience.

Many antifungal and antibacterial agents are used topically to treatepidermal infections. Some antibiotics, such as tetracycline andclindamycin, are also used to treat acne and other skin diseases thatare caused, directly or indirectly, by bacteria. One of the side-effectsof systemically administered clindamycin is colitis, which can bedangerous and even fatal. Thus, in treating acne, it is desirable toadminister clindamycin topically. Cleocin T®, manufactured byPharmacia-Upjohn, contains clindamycin phosphate, which is inactive invitro, but is hydrolyzed in vivo to the antibacterially activeclindamycin. Cleocin T® is currently available as a gel, a lotion, and atopical solution, and is used for topical treatment of acne vulgaris.

Others have produced topical formulations containing a pharmaceuticallyactive agent that is sparingly soluble to insoluble in water (e.g.,benzoyl peroxide) and a second pharmaceutically active agent (e.g.,clindamycin). For example, BenzaClin®, manufactured by DermikLaboratories, and Duac®, manufactured by Stiefel Laboratories, eachcontain benzoyl peroxide and clindamycin. BenzaClin® and Duac® arecurrently available as topical gels. Others have described a suspensionfoam containing benzoyl peroxide and clindamycin, but the foam containsoil and requires a surfactant in addition to a dispersing emulsifier.See, U.S. Patent Publication 2005/0186147.

Lotion, gels and oil-based foams have the disadvantage of extendedrub-in and may leave oily residues. The oil can also exacerbate acne.The solution form readily runs off the site of application, andtherefore it is difficult to apply controlled amounts using the solutionform.

The present subject matter provides a composition having at least onepharmaceutically active compound, which is useful for topicaladministration as described herein, as a foamable suspension gel that isnon-runny, easy to apply, and does not leave a noticeable residue. Thepresent foamable gel composition provides good control of theapplication of a small amount of product to the desired area.

SUMMARY OF THE INVENTION

The present subject matter provides an aqueous foamable suspension gelfor the topical administration of at least one active ingredient that issparingly soluble to insoluble in water. Thus, according to an aspect ofthe present subject matter, there is provided up to 40% w/w, forexample, 0.5-40%, 1-20%, 2-10%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%,25%, 30%, 35%, or 40%, of a first active agent that is sparingly solubleto insoluble in water, suspended in an aqueous phase and from about 0.1to about 2%, for example, 0.1%, 0.2%, 0.5%, 1.0%, 1.5%, or 2.0%, of oneor more thickening agents, wherein the gel is aqueous and forms ahomogeneous foam.

The present subject matter also provides aqueous, foamable suspensiongels for the topical administration of a first active ingredient that issparingly soluble to insoluble in water and a second active ingredient.

Accordingly, in another aspect, the present subject matter provides anaqueous, foamable suspension gel, comprising or consisting of:

-   -   up to 40% w/w, for example, 0.5-40%, 1-20%, 2-10%, 0.5%, 1%, 2%,        3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%, of a first        active agent that is sparingly soluble to insoluble in water,        suspended in an aqueous phase;    -   up to 40% w/w, for example, 0.1%-10%, 5-40%, 0.1%, 0.2%, 0.5%,        1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,        15%, 20%, 25%, 30%, 35%, or 40%, of a second active agent;    -   from about 0.1% to about 2%, for example, 0.1%, 0.2%, 0.5%,        1.0%, 1.5%, or 2.0%, of one or more thickening agents;    -   wherein the gel is aqueous and forms a homogenous foam.

In a further aspect, the present subject matter provides an aqueous,foamable suspension gel, comprising or consisting of:

-   -   up to 40% w/w, for example, 0.5-40%, 1-20%, 2-10%, 0.5%, 1%, 2%,        3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%, of a first        active agent that is sparingly soluble to insoluble in water,        suspended in an aqueous phase;    -   up to 40% w/w, for example, 0.1%-10%, 5-40%, 0.1%, 0.2%, 0.5%,        1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,        15%, 20%, 25%, 30%, 35%, or 40%, of a second active agent;    -   from about 0.1% to about 2%, for example, 0.1%, 0.2%, 0.5%,        1.0%, 1.5%, or 2.0%, of a thickening agent;    -   wherein the gel is aqueous, and has a viscosity of less than        about 20,000 centipoises (cP), and forms a homogenous foam.

In another aspect, the present subject matter provides an aqueous,foamable suspension gel, comprising or consisting of:

-   -   from about 1% to about 8% w/w benzoyl peroxide suspended in an        aqueous phase;    -   from about 0.025% to about 2% w/w of a retinoid; and    -   from about 0.5% to about 2% xanthan gum;    -   wherein the gel is aqueous and forms a homogenous foam.

In a further aspect, the present subject matter provides an aqueous,foamable suspension gel, comprising or consisting of:

-   -   from about 1% to about 25% w/w benzoyl peroxide as the sole        active ingredient present suspended in an aqueous phase; and    -   from about 0.5% to about 2% xanthan gum;    -   wherein the gel is aqueous and forms a homogenous foam.

In yet another aspect, the present subject matter provides an aqueous,foamable suspension gel, comprising or consisting of:

-   -   from about 1% to about 8% w/w of a first active ingredient        comprising benzoyl peroxide suspended in an aqueous phase;    -   from about 0.5% to about 4% w/w of a second active ingredient        comprising a retinoid in combination with clindamycin phosphate;        and    -   from about 0.5% to about 2% xanthan gum;    -   wherein the gel is aqueous and forms a homogenous foam.

In some embodiments, the foamable suspension gel is alcohol-free. Insome embodiments, the gel is a post-foaming gel that foams after releasefrom a container, for example, a pump or pressurized container.

In another aspect, the present subject matter provides methods fortreating a dermatological condition. A method for treating adermatological condition can comprise or consist of contacting the skinof an individual in need thereof with a foamable suspension gelaccording to the present subject matter. In some embodiments, themethods provide for the percutaneous treatment of acne.

In an embodiment, the present foamable suspension gel comprises orconsists of up to 40% w/w of a first active agent that is sparinglysoluble to insoluble in water, suspended in an aqueous phase andselected from the group consisting of benzoyl peroxide, a retinoid, anazole antimicrobial agent, and mixtures thereof; up to 40% w/w of asecond active agent selected from the group consisting of anantibacterial, an antifungal, an antibiotic, an immunomodulator, apeptide, a vitamin, a vitamin derivative, an azole, an oxide, andmixtures thereof; wherein if the first active agent is benzoyl peroxideand the second active agent is an antibiotic, then the foamablesuspension gel comprises an additional active ingredient.

In a still further embodiment, the first active agent is benzoylperoxide and the second active agent is sodium sulfacetamide. In afurther embodiment of the present subject matter, the first active agentis an azole antimicrobial agent and the second active agent is salicylicacid. In another embodiment, the first active agent is precipitatedsulfur and the second active agent is sodium sulfacetamide.

In another embodiment, the foamable suspension gel can comprise benzoylperoxide as the sole active ingredient. In some embodiments, the presentfoamable suspension gel can comprise or consist of a first active agentthat is sparingly soluble to insoluble in water, suspended in an aqueousphase; optionally a second active agent; optionally a third activeagent; one or more thickening agents; and optionally one or moreexcipients, for example, selected from the group consisting of adispersing/wetting agent, a pH-adjusting agent, a surfactant, asunfilter, a propellent, an antioxidant, an additional foaming agent, achelating/sequestering agent, a solvent, a fragrance, a coloring agent,a preservative, wherein the gel is aqueous and forms a homogenous foam.

In a further aspect, the present subject matter provides methods ofproducing aqueous, foamable suspension gels, the method can comprise orconsist of the following steps in any order:

-   -   suspending a first active agent in an aqueous phase, wherein the        first active agent is sparingly soluble to insoluble in water,        thereby forming a suspension;    -   increasing the viscosity of the suspension by adding a        sufficient amount of a thickening agent to hold the first active        agent in a suspension;    -   adding a second active agent, and

wherein the final viscosity of the foamable suspension gel is less thanabout 40,000 cP. The foamable suspension gel can contain alcohol or bealcohol-free.

In a further aspect, the present subject matter provides an aqueous,foamable suspension gel, that can comprise or consist of:

-   -   from about 1% to about 10% w/w benzoyl peroxide, suspended in an        aqueous phase;    -   from about 0.5% to about 2% clindamycin phosphate;    -   from about 1% to about 2% xanthan gum;    -   wherein the gel is aqueous, and forms a homogenous foam.

In a still further aspect, the present subject matter provides anaqueous foamable suspension gel, that can comprise or consist of:

-   -   from about 4% to about 8% w/w benzoyl peroxide as the sole        active ingredient present suspended in an aqueous phase;    -   from about 0.5% to about 2% xanthan gum;    -   wherein the gel is aqueous and forms a homogenous foam.

In another embodiment, the present subject matter provides an aqueousfoamable suspension gel, that can comprise or consist of:

-   -   from about 1% to about 8% w/w of a first active ingredient        comprising benzoyl peroxide suspended in an aqueous phase;    -   from about 0.5% to about 4% of a second active ingredient        comprising a retinoid in combination with clindamycin phosphate;    -   from about 0.5% to about 2% xanthan gum;

wherein the gel is aqueous and forms a homogenous foam.

In a further aspect, the present subject matter provides an aqueous,foamable suspension gel, that can comprise or consist of:

-   -   from about 4% to about 8% w/w benzoyl peroxide, suspended in an        aqueous phase;    -   from about 0.025% to about 2% of a retinoid;    -   from about 0.5% to about 2% xanthan gum;    -   wherein the gel is aqueous, and forms a homogenous foam.

The embodiments of the further compositions and methods are as describedabove and in the detailed embodiments, below.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates stability data of an exemplified foamable suspensiongel containing benzoyl peroxide and clindamycin having a pH of 5.0 andstored at 5° C.

FIG. 2 illustrates stability data of an exemplified foamable suspensiongel containing benzoyl peroxide and clindamycin having a pH of 5.0 andstored at 25° C.

FIG. 3 illustrates stability data of an exemplified foamable suspensiongel containing benzoyl peroxide and clindamycin having a pH of 4.5 andstored at 5° C.

FIG. 4 illustrates stability data of an exemplified foamable suspensiongel containing benzoyl peroxide and clindamycin having a pH of 4.5 andstored at 25° C.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless the context requires otherwise, the terms “active agent”, “activecompound,” “at least one pharmaceutically active compound” and“pharmaceutically active agent” are used interchangeably herein andrefer to a substance having a pharmaceutical, pharmacological ortherapeutic effect.

As used herein, the terms “administering”, “administration”, and liketerms refer to any method which, in sound medical or cosmetic practice,delivers the composition to a subject in such a manner as to provide anet positive effect.

The terms “antibiotic” and “antibacterial” are used hereininterchangeably to refer to a compound that inhibits the growth of,inhibits the virulence of, or kills bacterial cells. The term“antimicrobial” as used herein refers to a substance that kills orinhibits the growth of microbes such as bacteria (antibacterial), fungi(antifungal), viruses (antiviral) or parasites (anti-parasitic)Antibiotics include, e.g., substances produced by various species ofmicroorganisms (e.g., bacteria, fungi, and actinomycetes), variantsthereof, and synthetic antibacterial agents. Those of skill in the artare aware of the multitude of antibiotics that can be used in thepresent subject matter. See, e.g., Chapter 47 of Goodman & Gilman's ThePharmacological Basis of Therapeutics, Hardman and Limbard eds., 2001,McGraw-Hill; and Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Goodman, et al., eds., 2005, and Kucers, et al., The Useof Antibiotics: A Clinical Review of Antibacterial, Antifungal, andAntiviral Drugs, Oxford Univ. Press (1997).

The term “lincomycin antibiotic” as used herein refers to an antibioticoriginally recovered from Streptomyces lincolnensis. Exemplaryantibiotics include lincomycin and clindamycin and theirpharmaceutically acceptable salts and esters, including hydrochloridesand phosphates. The lincomycin antibiotics are described, for example,in U.S. Pat. Nos. 3,475,407; 3,509,127; 3,544,551 and 3,513,155.

The term “dispersing agent” as used herein refers to a surface-activeagent added to a suspending medium to promote uniform and maximumseparation of extremely fine solid particles, often of colloidal size.See, Lewis, Hawley's Condensed Chemical Dictionary, 14^(th) Edition,2002. A dispersing agent can also be expressed in terms of itshydrophile-lipophile balance (HLB) number. Similarly, the term “wettingagent” as used herein refers to a surface-active agent that, when addedto water, causes it to penetrate more easily into, or to spread over thesurface of, another material by reducing the surface tension of thewater. See, Lewis, Hawley's Condensed Chemical Dictionary, 14^(th)Edition, 2002. A wetting agent can also be expressed in terms of its HLBnumber. As contemplated herein, a single surface-active agent couldpotentially have activity as any or all of a surfactant, a dispersingagent, and a wetting agent.

As used herein, the phrases an “effective amount” or a “therapeuticallyeffective amount” of an active agent or ingredient, or pharmaceuticallyactive agent or ingredient, which are synonymous herein, refer to anamount of the pharmaceutically active agent sufficient enough to have anet positive effect upon administration. A therapeutically effectiveamount of the pharmaceutically active agent will cause a substantialrelief of symptoms when administered repeatedly over time. Effectiveamounts of the pharmaceutically active agent will vary with theparticular condition or conditions being treated, the severity of thecondition, the duration of the treatment, the specific components of thecomposition being used, and like factors.

The term “foamable” as used herein refers to the composition being ableto form a foam. It can be worked or lathered into a foam, for examplefollowing application to wet or dry skin. It can form a foam whendispensed from a device that allows air or vapor to be entrapped withinthe gel during dispensing, for example, an air aspirated foamingdispenser. It can form a foam when dispensed from an aerosol container,for example, wherein a liquefied propellant mixed with the suspensiongel facilitates the production of the foam.

As used herein, “homogeneous” or “homogenous” refer to substantiallyuniform throughout, i.e., a uniform mixture.

The term “pH” as used herein refers to the value given by a suitable,properly standardized, potentiometric instrument (pH meter) capable ofreproducing pH values to 0.02 pH units using an indicator electrodesensitive to hydrogen-ion activity, a glass electrode, and a suitablereference electrode. Where approximate pH values suffice, alternateelectrodes, pH indicators and/or test papers can be used.

As used herein, the phrase “Pharmaceutically acceptable salt” of anactive compound means a salt that is pharmaceutically acceptable andthat possesses the desired pharmacological activity of the parentcompound. Such salts include: (1) acid addition salts, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like; or (2) salts formed when an acidic proton present in theparent compound either is replaced by a metal ion, e.g., an alkali metalion, an alkaline earth metal ion, or an aluminum ion; or (3) coordinateswith an organic base such as ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, and the like.

As used herein, the term “prodrug” refers to any compound which releasesan active agent in vivo when such prodrug is administered to a subject.Prodrugs of an active agent are prepared by modifying one or morefunctional group(s) present in the active agent in such a way that themodification(s) may be cleaved in vivo to release the parent compound.Prodrugs include compounds wherein a hydroxy, amino or sulfhydryl groupin the active agent is bonded to any group, e.g., protecting group, thatmay be cleaved in vivo to regenerate the free hydroxyl, amino orsulfhydryl group, respectively. Examples of prodrugs include, but arenot limited to, active agents whose functional group(s) are protected byone or more protecting groups listed in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley &Sons, New York, 1999, and Harrison and Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996),which are incorporated herein by reference in their entirety.Representative hydroxy protecting groups which are useful in preparingprodrugs include acyl groups (e.g., formyl, acetyl and trifluoroacetyl),alkyl ethers, phosphate ethers, phosphate esters, and the like.Representative amino protecting groups that are useful in preparingprodrugs include acyl groups (e.g., formyl, acetyl, andtrifluoroacetyl), benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc),and the like.

The term “solubility” or “soluble” as used herein refers to the amountof a substance (e.g. a solid) that will dissolve in another substance(e.g., a liquid). Solubility is generally determined at temperaturesbetween 15° C. and 25° C. and expressed as w/v. As used herein,solubility ranges of solute in liquid are as follows:

very soluble 1 in less than 1 freely soluble 1 in 1 to 1 in 10 soluble 1in 10 to 1 in 30 sparingly soluble 1 in 30 to 1 in 100 slightly soluble1 in 100 to 1 in 1000 very slightly soluble 1 in 1000 to 1 in 10,000practically insoluble or insoluble 1 in more than 10,000Solubility ranges are available in published pharmacopoeias, includingUnited States Pharmacopoeia (USP), European Pharmacopoeia (EP), BritishPharmacopoeia (BP); and in Martindale: The Complete Drug Reference,Sweetman, 2004, Pharmaceutical Press., and in Martindale, Martindale:The Extra Pharmacopoeia, 31st Edition., 1996, Amer Pharmaceutical Assn,which is herein incorporated by reference.

The term “treating” as used herein refers to the process of producing aneffect on biological activity, function, health, or condition of anorganism in which such activity is maintained, enhanced, diminished, orapplied in a manner consistent with the general health and well-being ofthe organism.

The term “vehicle” as used herein refers to a composition which has onlyexcipient or components required to carry an active agent, but whichitself has no pharmaceutical or therapeutic effect.

Other terms as used herein are meant to be defined by their well-knownmeanings in the art.

Foamable Pharmaceutical Compositions

The present subject matter provides simple and elegant foamablesuspension gels that surprisingly maintain the chemical and physicalstability of at least one active agent in a suspension that forms ahomogenous foam. The foamable suspension gels are aqueous andoptionally, alcohol-free and/or oil-free. The present suspension gelsare foamable, break down with mechanical shear, but are not so-calledalcoholic “quick-break” foams.

Moreover, the gel formulation in the can or container can be apost-foaming gel, which foams once released from the can. Thisinnovative formulation provides extended shelf-life coupled with ease ofapplication. For example, benzoyl peroxide is known to degradeclindamycin. However, the current foamable suspension gel formulationadvantageously provides for both stability and ease of application.

In some embodiments, the foamable suspension gel is oil-free. In thisregard, the phrase “oil-free” as used herein refers to compositionscontaining less than 1% by weight oil. In some embodiments, the foamablesuspension gel is alcohol-free. In this regard, the phrase“alcohol-free” as used herein refers to compositions containing lessthan 1% by weight alcohol. Alcohol in this regard includes ethanol,isopropanol, n-propanol, butanol, or any other short chain aliphaticalcohol. In some embodiments, the foamable suspension gel is oil-freeand alcohol-free.

a. Components

Components of the present foamable suspension gels can comprise orconsist of a first active agent sparingly soluble to insoluble in water,an aqueous phase, a thickening agent, and water. The foamable suspensiongels can comprise a second active agent. Optionally, the foamablesuspension gels include one or more of a pH-adjusting agent (e.g., anacid, a base, a buffering agent, a buffering pair), a wettingagent/dispersing agent, a surfactant, a sun filter, a third activeagent, an antioxidant, an additional foaming agent, a chelatingsequestering agent, or a propellant. The foamable suspension gels can bealcohol-free and/or oil-free.

i. Active Agents

1. First Active Agent

The first active agent in the foamable suspension gel is sparinglysoluble to insoluble in water, and is dispersed or suspended in theaqueous phase. Exemplified categories of active agents that aresparingly soluble to insoluble in water include, for example,analgesics, anesthetics, anti-inflammatory agents, antipyretics,antimicrobial agents such as, for example, antibacterial agents,antibiotics, and antifungals, antidepressants (e.g., nortriptylinehydrochloride), antiepileptics (e.g., methsuximide, phenobarbital,primidone), antimalerial agents (e.g., quinine sulfate), antimigraineagents (e.g., dihydroergotamine mesylate, ergotamine tartrate,methysergide maleate), antineoplastic agents (e.g., testolactone),immunosuppressants, antiprotozoal agents (e.g., metronidazole),antianxiolytic agents, antipsychotics, antihistamines, cardiovascularagents, corticosteroids, sex hormones, cough suppressants (e.g.,dextromethorphan hydrobromide, guaifenesin, terpin hydrate),dermatological agents, diagnostic agents (e.g., indigotindisulfonatesodium), disinfectants, dopaminergic agents (e.g., apomorphinehydrochloride), antimuscarinic agents (e.g., atropine, isopropamideiodide, procyclidine hydrochloride), parasympathomimetics (e.g.,physostigmine salicylate), sympathomimetics (e.g., xylometazolinehydrochloride, isoxsuprine hydrochloride), thyroid and antithyroidagents (e.g., iodine, levothyroxine sodium), skeletal muscle relaxants(e.g., carisoprodol, methocarbamol), stimulants and anorexiants (e.g.,doxapram hyfrochloride), gastrointestinal agents, immunomodulators,peptides, vitamins and vitamin derivatives, azoles, oxides and xanthines(e.g., caffeine), salts or derivatives thereof, and mixtures thereof.

In some preferred embodiments, the first active agent is selected fromthe group consisting of an antibacterial, an antibiotic, an antifungal,an immunomodulator, a peptide, a vitamin, a vitamin derivative, anazole, an oxide, salts or derivatives thereof, and mixtures thereof. Insome embodiments, the first active agent is selected from the groupconsisting of benzoyl peroxide, a retinoid, a steroid, an azoleantimicrobial agent, precipitated sulfur, and mixtures thereof.

Suitable concentration ranges of the first pharmaceutically activecompound can be, for example, up to about 40% w/w, for example, in therange of about 0.5-40%, 1-20%, 2-10% w/w, or about 0.5%, 0.8%, 1%, 1.5%,2%, 2.5%, 3%, 5%, 7.5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% w/w.

In some embodiments, the first active agent is benzoyl peroxide (BPO),that can be present in an amount from about 1% to about 25%, from about1% to about 8%, from about 2% to about 8%, from about 4% to about 8%,from about 4% to about 10% for example, about 1%, 1.5%, 2%, 2.5%, 3%,4%, 5%, 6%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 15%, 20%, or 25%.

Exemplified analgesics, anti-inflammatory agents and antipyreticsinclude, for example, aminohippuric acid, anileridine, aspirin, codeine,codeine sulfate, indomethacin, levorphanol tartrate, pentazocine,pentazocine hydrochloride, propoxyphene napsylate, salts or derivativesthereof, and mixtures thereof.

Exemplified anesthetics include, for example, benzocaine, butamben,cocaine, dibucaine, dyclonine hydrochloride, tetracaine, salts orderivatives thereof, and mixtures thereof.

Exemplified antibacterial agents include, for example, chloramphenicol,chlortetracycline hydrochloride, clioquinol, demeclocycline,demeclocycline hydrochloride, erythromycin, methacycline hydrochloride,nalidixic acid, nitrofurazone, oxytetracycline, oxytetracycline calcium,penicillins (e.g., penicillin G, penicillin G benzathine, penicillin Gsodium, and penicillin V benzathine), pyrazinamide, sulfadiazine,sulfamethizole, sulfamethoxazole, sulfapyridine, sulfisoxazole,tetracycline, salts or derivatives thereof, and mixtures thereof.

Exemplified antihistamines include, for example, cyclizinehydrochloride, cyproheptadine hydrochloride, hydroxyzine pamoate,phenindamine tartrate, thiethylperazine maleate, salts or derivativesthereof, and mixtures thereof.

Exemplified anti-anxiolytics include, for example, chlordiazepoxide,diazepam, droperidol, haloperidol, oxazepam, pentobarbital, pimozide,thiothixene, triazolam, salts or derivatives thereof, and mixturesthereof.

Exemplified cardiovascular agents include, for example, acenocoumarol,acetyldigitoxin, apraclonidine hydrochloride, enalaprilat,hydroflumethiazide, methyclothiazide, nifedipine, quinidine sulfate,trichlormethiazide, salts or derivatives thereof, and mixtures thereof.

Exemplified corticosteroids include, for example, betamethasone,betamethasone acetate, betamethasone valerate, clobetasol propionate,desonide, flumethasone pivalate, fluocinolone acetonide,fluorometholone, methylprednisolone, methylprednisolone acetate,prednisolone, prednisolone acetate, prednisolone hemisuccinate,prednisone, salts or derivatives thereof, and mixtures thereof.

Exemplified dermatological agents include, for example, abrasive agents,acitretin, adapalene, benzoyl peroxide, calamine, calcipotriene,dithranol, etretinate, fumaric acid, isotretinoin, metal oxides, pumice,pyrithione zinc, salicylic acid, selenium sulfide, precipitated sulfur,tacalcitol, talc, tars, titanium dioxide, tretinoin, zinc oxide, saltsor derivatives thereof, and mixtures thereof.

Exemplified disinfectants include, for example, ascorbyl palmitate,benzoic acid, chlorobutanol, chlorocresol, chloroxylenol, halazone,methylparaben, nitromersol, phenylmercuric acetate, phenylmercuricnitrate, propylparaben, sorbic acid, thymol, salts or derivativesthereof, and mixtures thereof.

Exemplified vitamins and nutritional agents include, for example,vitamin A, vitamin E, vitamin K, cyanocobalamin, hydroxocobalamin,niacin, saccharin, thiamine mononitrate, salts or derivatives thereof,and mixtures thereof.

Exemplified sex hormones include, for example, dydrogesterone, estradiolcypionate, estropipate, norethindrone acetate, oxandrolone,oxymetholone, stanozolol, salts or derivatives thereof, and mixturesthereof.

Exemplified gastrointestinal agents include, for example, bisacodyl,docusate calcium, docusate sodium, magnesium hydroxide, sennosides,sulfasalazine, salts or derivatives thereof, and mixtures thereof.

Other active agents of interest that are sparingly soluble to insolublein water include, for example, betadex, calcium hydroxide, calciumsulfate, camphor, disulfiram, ethyl vanillin, methylergonovine maleate,papaverine hydrochloride, sucrose octaacetate, vanillin, salts orderivatives thereof, and mixtures thereof.

Further examples of sparingly soluble to insoluble active agents can befound, for example, in Martindale: The Complete Drug Reference,Sweetman, 2004, Pharmaceutical Press., and in Martindale, Martindale:The Extra Pharmacopoeia, 31st Edition., 1996, Amer. PharmaceuticalAssn., which is herein incorporated by reference.

In one embodiment, the first active agent is benzoyl peroxide. BenzoylPeroxide (CAS No. 94-36-0) can be commercially purchased from, forexample, Sigma-Aldrich Chemicals, St. Louis, Mo.

In one embodiment, the first active agent is one or more azoleantimicrobial or antifungal agents, for example, one or more of animidazole or a triazole, including nitrate forms. The imidazole can be,for example, clotrimazole, miconazole, metronidazole, ketoconazole,econazole, butoconazole, oxiconazole, sulconazole, or mixtures thereof.The triazole can be, for example, albaconazole, ravuconazole,voriconazole, posaconazole, terconazole, itraconazole, and fluconazole.In one embodiment, the azole antimicrobial is metronidazole. In oneembodiment, the azole antimicrobial is ketoconazole. Further informationregarding azole antimicrobials can be found, for example, in Goodman andGilman's The Pharmacological Basis of Therapeutics, Goodman, et al.,eds., 11th Edition, 2005, McGraw-Hill. Additional antimicrobial agentsand/or antifungal agents are further contemplated as useful herein,including by way of non-limiting example ciclopirox, ciclopirox olamine,terbinafine, tea tree oil, griseofulvin, undecylenic acid, salicylicacid, tolnaftate, amphotericin, candicidin, flucytosine, natamycin,nystatin, undecenoic acid, salts or derivatives thereof, and mixturesthereof.

In one embodiment, the first active agent is one or more retinoids, forexample, vitamin A, retinol (cis or trans), retinal (cis or trans),retinoic acid (cis), tretinoin, hydroxyretroretinol, didehydroretinoicacid, etretinate, retinyl palmitate, β-carotene, tazarotene, acitretin,adapalene, salts or derivatives thereof, and mixtures thereof. Furtherinformation regarding retinoids can be found, for example, in Goodmanand Gilman's The Pharmacological Basis of Therapeutics, supra.

2. Second Active Agent

The second active agent can be any pharmaceutically active agentsuitable for topical administration. The second active agent can besoluble in water, or sparingly soluble to insoluble in water. The secondactive agent can effect a pharmaceutical response that complements thefirst active agent, or that is independent of the first active agent, asdesired. The second active agent can be, for example, antimicrobialagents such as antibacterials, antibiotics, and antifungals,immunomodulators, peptides, vitamins and vitamin derivatives, azoles,oxides, salts or derivatives thereof, and mixtures thereof. In oneembodiment, the second active agent is an anti-acne agent.

In one embodiment, the second active agent is selected from the groupconsisting of a lincomycin antibiotic (e.g., clindamyin, lincomycin), aretinoid, sodium sulfacetamide, or salicylic acid.

Suitable concentration ranges of the second pharmaceutically activecompound can be, for example, up to about 2%, 5%, 7%, 10%, 12%, 15%,20%, 25%, 30%, 35%, or 40% w/w, for example, in the range of about0.01-10%, 0.1-8%, 0.2-5%, 0.5-2%, or 5-40% w/w, or about 0.1%, 0.2%,0.5%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 5%, 6%, 7%, 7.5%, 8%, 8.5%, 9%,9.5%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, or 40% w/w.

In one embodiment, the second active agent is clindamycin, apharmaceutically acceptable salt or prodrug thereof. Clindamycin is anantibiotic also known as methyl7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto-octo-pyranosideor methyl7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]amino]-1-thio-L-threo-α-D-galacto-octo-pyranoside.As used herein, the term “clindamycin” alone includes free-baseclindamycin as well as the pharmaceutically acceptable salts and estersthereof. Examples of pharmaceutically acceptable salts and esters ofclindamycin include, but are not limited to, clindamycin hydrochloride,clindamycin phosphate, clindamycin palmitate, and clindamycin palmitatehydrochloride. A clindamycin salt or ester can be used in the presentcompositions, for example, clindamycin phosphate.

The uses, properties, and methods of synthesis of clindamycin are setforth in U.S. Pat. No. 3,969,516, Stoughton, issued Jul. 13, 1976; U.S.Pat. No. 3,475,407, Bierkenmeyer, issued in 1969; U.S. Pat. No.3,487,068, issued in 1969; U.S. Pat. Nos. 3,509,127 and 3,544,551, Kaganand Magerlein, issued in 1970; U.S. Pat. No. 3,513,155, Bierkenmeyer andKagan, issued in 1970; Morozowich and Sinkula, U.S. Pat. No. 3,580,904,issued in 1971 and U.S. Pat. No. 3,655,885, issued in 1972; U.S. Pat.No. 3,714,141, issued in 1973; U.S. Pat. No. 4,568,741, issued in 1986;and U.S. Pat. No. 4,710,565, issued in 1984. All of the foregoingpatents are hereby incorporated herein by reference.

Additional knowledge in the art concerning clindamycin is found in, forexample, Magerlein, et al., Antimicro. Ag. Chemother. 727 (1966);Birkenmeyer and Kagan, J. Med. Chem., 13, 616 (1970); Oesterling, J.Pharm Sci. 59, 63 (1970); McGehee, et al., Am. J. Med. Sci. 256, 279(1968); D. A. Leigh, J. Antimicrob. Chemother. 7 (Supplement A), 3(1981); J E Gray et al., Toxicol. Appl. Pharmacol. 21, 516 (1972), and LW Brown and W F Beyer in Analytical Profiles of Drug Substances, Vol.10, K. Florey, editor (Academic Press, New York, 1981), pages 75-91.

Clindamycin phosphate and clindamycin hydrochloride are commerciallyavailable from, for example, Sigma-Aldrich, St. Louis, Mo. and AbbottLaboratories, Chicago, Ill.

In one embodiment, the second active agent is one or more retinoids, forexample, vitamin A, retinol (cis or trans), retinal (cis or trans),retinoic acid (cis), tretinoin, hydroxyretroretinol, didehydroretinoicacid, etretinate, retinyl palmitate, β-carotene, tazarotene, acitretin,adapalene, salts or derivatives thereof, and mixtures thereof.

In one embodiment, the second active agent is sodium sulfacetamide.

In some embodiments, the first active agent and the second active agentare the same, but the first active agent is suspended and the secondactive agent is dissolved or solubilized. In this manner, the suspendedfirst active agent has a different rate of release than the solubilizedsecond active agent. By tailoring the rate of release, it is possible toadvantageously effect the rate of penetration of the active ingredient.For example, in certain embodiments, the solubilized active agentpenetrates faster into the epidermis whereas the suspended active agentexhibits slow release and therefore slower penetration. Those of skillin the art will know of other ways to tailor the active agents in orderto manifest beneficial rates of penetration.

In some embodiments, the second active agent is selected from the groupconsisting of an antibacterial, an antibiotic, an antifungal, animmunomodulator, a peptide, a vitamin, a vitamin derivative, an azole,an oxide, salts or derivatives thereof, and mixtures thereof. In someembodiments, the second active agent is selected from the groupconsisting of a lincomycin antibiotic, a retinoid, sodium sulfacetamide,salicylic acid, salts or derivatives thereof, and mixtures thereof. Insome embodiments, the second active agent is a lincomycin antibiotic,for example, lincomycin or clindamycin, salts or derivatives thereof, ormixtures thereof, or a macrolide antibiotic, by way of non-limitingexample, clarithromycin, azithromycin, erythromycin, salts orderivatives thereof, or mixtures thereof. In one embodiment, the secondactive agent is clindamycin phosphate, which can be present in an amountfrom about 0.2% to about 2.5%, for example, about 0.2%, 0.5%, 0.8%, 1%,1.5%, 2%, or 2.5%.

As desired, the second active agent can be soluble or sparingly solubleto insoluble in water. The second active agent can be dissolved,solubilized or in a suspension.

In some embodiments, the first active agent or the second active agentis a retinoid. In some embodiments, the retinoid is selected from thegroup consisting of vitamin A, retinol (cis or trans), retinal (cis ortrans), retinoic acid (cis), tretinoin, hydroxyretroretinol,didehydroretinoic acid, etretinate, retinyl palmitate, β-carotene,tazarotene, acitretin, adapalene, salts or derivatives thereof, andmixtures thereof.

In one embodiment, the first active agent is benzoyl peroxide and thesecond active agent is clindamycin phosphate. In another embodiment, thefirst active agent is tretinoin and the second active agent isclindamycin phosphate. In a further embodiment, the first active agentis metronidazole and the second active agent is sodium sulfacetamide. Inanother embodiment, the first active agent is benzoyl peroxide and thesecond active agent is tretinoin.

In some embodiments, wherein if the second active agent comprises anantibiotic, the second active agent preferably comprises an additionalactive agent. In some embodiments the second active agent comprises orconsists of one or more antibiotics and an additional active agent.

3. Third Active Agent

In some embodiments, the foamable suspension gels further comprise athird active agent. The third active agent can be any pharmaceuticallyactive agent suitable for topical administration. The third active agentcan be soluble in water, or sparingly soluble to insoluble in water.

In some embodiments, the third active agent can be, for example,antibacterials, antibiotics, antifungals, immunomodulators, peptides,vitamins and vitamin derivatives, azoles, oxides, salts or derivativesthereof, and mixtures thereof. In some embodiments, the third activeagent is a topically applied anti-acne agent different from either thefirst or second active agents. Any topical anti-acne agent known in theart can be included as a third active agent in the foamable suspensiongels. Exemplified anti-acne agents include retinoids, antibiotics, azoleantimicrobials, vitamins, and the like.

In some embodiments, the anti-acne agent is an antibiotic, anantimicrobial azole, a retinoid, or a vitamin (e.g., a vitamin A, avitamin B, a vitamin C, a vitamin E). As desired, the third active agentcan be soluble or sparingly soluble to insoluble in water. The thirdactive agent can be dissolved, solubilized or suspended in the gel.

In some embodiments, the third active agent is a sun filter, asdescribed below.

ii. Dispersing Agents/Wetting Agents

Active agents that are sparingly soluble to insoluble in water (i.e.,are hydrophobic), can require a dispersing agent or wetting agent tocoat the surface of the hydrophobic particles, thereby lowering theirsurface tension. The dispersing agent and the wetting agent can be thesame agent or two or more different agents. A dispersing/wetting agentcan help to maintain the hydrophobic particles in the formulation matrixand aiding in the distribution of the hydrophobic active agent upon theskin. U.S. Pat. No. 5,470,884 discusses the benefits of adispersing/wetting agent with reference to formulations containingbenzoyl peroxide.

In some embodiments, the aqueous phase can comprise a dispersing/wettingagent. The dispersing/wetting agent can be provided to facilitate thesuspension of the first active agent in the aqueous phase. In someembodiments, the dispersing/wetting agent is a surfactant.

In the foamable suspension gels of the present subject matter, activeagents sparingly soluble to insoluble in water are suspended in theaqueous phase. Suspension can be facilitated by inclusion of adispersing/wetting agent in the aqueous phase. The dispersing/wettingagent allows the sparingly soluble to insoluble active agent to bedispersed or wetted with water.

The dispersing/wetting agents can have surfactant properties. Suitabledispersing/wetting agents break up the majority of the hydrophobicparticles of the active agent sparingly soluble to insoluble in waterinto primary particle form and allow for easy redispersion of settledparticles.

In some embodiments, the dispersing/wetting agent is a non-ionicsurfactant. Exemplified dispersing/wetting agents for use in the presentfoamable suspension gels include sodium dioctyl sulfosuccinate, Brij®-30(Laureth-4), Brij®-58 (Ceteth-20) and Brij®-78 (Steareth-20), Brij®-721(Steareth-21), Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40),Crillet-3 (Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40Stearate), Myrj-53 (PEG-50 Stearate), Pluronic® F77 (Poloxamer 217),Pluronic® F87 (Poloxamer 237), Pluronic® F98 (Poloxamer 288), Pluronic®L62 (Poloxamer 182), Pluronic® L64 (Poloxamer 184), Pluronic® F68(Poloxamer 188), Pluronic® L81 (Poloxamer 231), Pluronic® L92 (Poloxamer282), Pluronic® L101 (Poloxamer 331), Pluronic® P103 (Poloxamer 333),Pluracare® F 108 NF (Poloxamer 338), and Pluracare® F 127 NF (Poloxamer407). In some embodiments, the dispersing/wetting agent is Pluronic® F68(Poloxamer 188). In one embodiment, the dispersing/wetting agent is aPluronic® (Poloxamer). In one embodiment, the dispersing/wetting agentis Pluronic® F68 (Poloxamer 188). Pluronic® polymers are commerciallypurchasable from BASF, USA and Germany.

A wide variety of other surfactants can also be employed in the presentfoam compositions, if desired. These surfactants can include, forexample, polyoxyethylene fatty ethers, polyoxyethylene fatty esters,fatty acids, sulfated fatty acids, phosphated fatty acids,sulfosuccinates, amphoteric surfactants, non-ionic poloxamers, non-ionicmeroxapols, petroleum derivatives, aliphatic amines, polysiloxanederivatives, sorbitan fatty acid esters, pharmaceutically acceptablesalts thereof, and mixtures thereof. In particularly preferredembodiments in this regard, the surfactant can be selected from thegroup consisting of laureth-4, PEG-2 dilaurate, stearic acid, sodiumlauryl sulfate, dioctyl sodium sulfosuccinate, cocoamphopropionate,poloxamer 188, meroxapol 258, triethanolamine, dimethicone, polysorbate60, sorbitan monostearate, pharmaceutically acceptable salts thereof,and mixtures thereof.

Other surfactants commonly known as useful in the preparation offoamable compositions are further contemplated as within the scope ofthe present subject matter. These other surfactants include, forexample, those listed in the CTFA Cosmetic Ingredient Dictionary, SecondEdition, The Cosmetic Toiletry and Fragrance Association, Inc., 1133Fifteenth Street, N.W., Washington, D.C. 20005, 1977, the entirecontents of which are hereby incorporated by reference.

The foamable suspension gels generally contain up to about 1%, 2%, 3%,4%, 5% (w/w) dispersing/wetting agent, for example in the range of0.2-5%, 0.5-3%. In some embodiments, the foamable suspension gelscontain about 0.2%, 0.5%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, or 5%dispersing/wetting agent.

In some embodiments, the dispersing/wetting agents possess surfactantproperties, and the foaming suspension gels do not require an additionalsurfactant. Generally, inclusion of a surfactant is optional.

In some embodiments, the thickening agent can be used as a dispersingagent in addition to a thickening agent. In such formulations, thefoaming suspension gels do not require a distinct dispersing/wettingagent or an additional surfactant. Addition of a distinctdispersing/wetting agent or an additional surfactant is optional.

A dispersing and/or wetting agent is not generally considered to be afoaming agent. In fact, foaming can be a disfavored attribute for thesetypes of surfactants. Efficient wetting of a surface occurs when thecohesive forces between hydrophobic regions of adsorbed surfactantmolecules are minimized. Cohesion between hydrophobic regions isminimized by increasing the size of the hydrophilic region(s) relativeto the hydrophobic region(s) for a given wetting agent. Similarly,decreasing the size of the hydrophobic region(s) relative to thehydrophilic region(s) minimizes the cohesion between hydrophobicregions. For good foaming to occur, the cohesive forces between adsorbedsurfactant molecules must be greater than the cohesive forces requiredfor good wetting. Therefore a good wetting agent is typically considereda poor foaming agent and vice versa. See, page 218 of Schönfeldt,Surface Active Ethylene Oxide Adducts, 1969, Pergamon Press.

iii. Thickening Agents

The foamable suspension gels contain one or more thickening orsuspension agents that provide a suitable viscosity and are in an amountthat is sufficient to hold the active agent which is sparingly solubleto insoluble in water in a suspension. The thickening agent can besubstantially chemically inert. The thickening agent can be synthetic ornaturally occurring.

The amount of thickening agent is sufficient to maintain the activeagent which is sparingly soluble to insoluble in water in suspension,while maintaining a pourable gel that can be efficiently and evenlyreleased from a container. The foamable suspension gels can contain upto about 5% thickening agent, usually up to about 3% or 2% thickeningagent. In some embodiments, the foamable suspension gels contain in therange of about 0.1-2%, 0.8-1.5% thickening agent, for example, about0.1, 0.2, 0.5, 0.8, 1, 1.3, 1.5, 2% thickening agent. In someembodiments, the amount of thickening agent included will result in afoamable gel having a viscosity of less than about 40,000 centipoises(cP), for example, in the range of about 1,000 to about 20,000 cP.

The thickening agent can be substantially chemically inert to otheringredients. The thickening agent can be synthetic or naturallyoccurring. In some embodiments, the thickening agent is a hydrocolloid,for example, selected from the group consisting of agar, alginate,arabinoxylan, carrageenan, carboxymethylcellulose, hydroxypropylmethylcellulose, cellulose, curdlan, gelatin, gellan, β-glucan, guargum, gum arabic, locust bean gum, pectin, starch, a carbomer, acrylatecopolymers, silica, xanthan gum, salts or derivatives thereof, andmixtures thereof. In some embodiments, the thickening agent is a naturalgum, for example, selected from the group consisting of gum arabic,tragacanth gum, xanthan gum, carrageenan (alginate gum), pectin, guargum, salts or derivatives thereof, and mixtures thereof.

In some embodiments, the thickening agent is xanthan gum or a carbomer.In some embodiments, the thickening agent is xanthan gum. In someembodiments, the thickening agent can be selected from the groupconsisting of a hydrocolloid, a natural gum, and mixtures thereof.

In some embodiments, the thickening agent is xanthan gum. The xanthangum can be food grade or a pharmaceutical grade (USP/NF). Exemplifiedxanthan gums suitable for use in the present foamable suspension gelsinclude Keltrol F, Xantural 11K, Xantural 75, Xantural 180. Food gradeand pharmaceutical/cosmetic grade xanthan gum formulations arecommercially available from, for example, CP Kelco, Atlanta, Ga.

iv. Water

The present foamable suspension gels are aqueous.

The foamable suspension gels contain at least about 20%, 30%, 40%, 50%,60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, 99% water. In some embodiments, the foamablesuspension gels contain in the range of about 86-95%, 87-94%, 87-95%,88-93%, or 89-92% water. In some embodiments, the foamable suspensiongel comprises at least about 30% water.

Water content can be measured using techniques well known in the art,including for example, using a coulometer (Metrohm KF, Herisau,Switzerland).

v. pH-Adjusting Agents

The foamable suspension gels can comprise a pH-adjusting agent, forexample, an acid, a base, a buffering pair, or a buffering agent. Insome embodiments, the pH-adjusting agent is a buffering agent, forexample, a buffering pair to stably maintain a desired pH. The chosenbuffering agent or buffering pair selected will depend on the activeingredients included in the gel. An appropriate buffer may have a pKavalue that is at or near the desired pH.

In some embodiments, the desired pH is an acidic pH. Exemplifiedbuffering agents to maintain an acidic pH include, for example, citricacid/citrate, acetic acid/acetate, BICINE, HEPES, Trizma. In someembodiments, the desired pH is a neutral pH. Exemplified bufferingagents to maintain a neutral pH include HEPES, TRIS, phosphoricacid/phosphate, Trizma. In some embodiments, the desired pH is a basicpH. Exemplified buffering agents to maintain a basic pH include TRIS,Trizma, HEPES, carbonate/bicarbonate. These and additional biologicalbuffers are available from Sigma-Aldrich, St. Louis, Mo. or Merck,Darmstadt, Germany. The buffering agent can also be an amino acid, forexample, glycine, histidine, arginine, lysine, asparagine, asparticacid, glutamine, glutamic acid. In certain instances, it may beappropriate to add an acid or a base, for example, HCl, NaOH, KOH toarrive at the proper pH value.

In formulations including benzoyl peroxide and clindamycin, thebuffering pair can be citric acid and citrate.

The buffering agent or buffering pair can be included at a concentrationof up to about 1%, usually up to about 0.3%, 0.5%, 0.7%, or in a rangeof about 0.1-1.0%, 0.3-0.8%. The foamable suspension gels can containabout 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (w/w) of abuffering agent or a buffering pair.

In some embodiments, the pH-adjusting agent is a buffering agent or abuffering pair, for example, an amino acid, a citrate buffer, aphosphate buffer, a bicarbonate buffer, a TRIS buffer, or a HEPESbuffer. In some embodiments, the foamable suspension gel has a pHbetween about 3-9, about 4-9, about 4-6, or about 4-5.5. In someembodiments, the foamable suspension gel has a pH of about 4, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4 or 5.5.

vi. Antioxidants

In some embodiments, the foamable suspension gels can comprise one ormore antioxidants or free radical scavengers to maintain the desiredphysical and chemical properties. Suitable antioxidants do notthemselves initiate the decomposition of an active agent, and aresoluble in the present formulations. Exemplified antioxidants includeoxygen, quinones, co-enzyme Q, polymerizable monomers, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid,ascorbyl palmitate, t-butyl hydroquinone, disodium ethylenediaminetetraacetic acid (EDTA), erythorbic acid, olive (olea eurpaea) oil,pentasodium penetetate, pentetic acid, propyl gallate, sodium ascorbate,sodium metabisulfite, sodium sulfite, tocopheryl, and tocopherylacetate.

An antioxidant can be included at a concentration up to about 0.5%, moreusually up to about 0.1% or 0.2% (w/w), for example, about 0.1%, 0.15%,0.2%, 0.25%, 0.3%, 0.4%, or 0.5%.

Inclusion of an antioxidant is optional. In some embodiments, thefoamable suspension gels are free of an antioxidant.

vii. Chelating/Sequestering Agents

Chelating and sequestering agents can aid in delaying the initiation offree radical formation with divalent trace metal cations. Including achelating agent into the formulation can be advantageous in formulationsthat are packaged in a metal container. An exemplifiedchelating/sequestering agent is ethylenediamine tetraacetic acid (EDTA).

A chelating/sequestering agent can be included at a concentration up toabout 0.5%, more usually up to about 0.1% or 0.2% (w/w), for example,about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5%.

viii. Sun Filters

In some embodiments the foamable suspension gels of the present subjectmatter further comprise one or more sun filters, sunscreen, sunblock, orany other sun-blocking components or agents. Any sun filters known inthe art are suitable in the present compositions, including UVA and/orUVB sun filters.

Exemplified sun filters include include Aminobenzoic acid(4-Aminobenzoic acid); Avobenzone(4-tert-butyl-4-methoxydibenzoylmethane); Benzophenone-2 (Bis(2,4-Dihydroxyphenyl) Methanone); Benzophenone-3 (Oxybenzone);Benzophenone-4 (Sulisobenzone); Benzophenone-5 (Sulisobenzone sodium);Benzophenone-8 (Dioxybenzone); BenzylideneCamphor(3-(4-Methylbenzylidene)-d-1 camphor); Cinoxate; Ecamsule(Terephthalylidene dicamphor sulfonic acid); Ethoxylated ethyl4-aminobenzoic acid (PEG25 PABA, e.g., Uvinul® P25); Homosalate(Homomethyl salicylate); Isoamylmethoxycinnamate(Isopentenyl-4-methoxycinnamate); Isopropylbenzyl salicylate; Menthylanthranilate (Methyl 2-aminobenzoate); Mexoryl XL (phenol,2-(2H-benzotriazol-2-yl)-4-methyl-6[2-methyl-3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl) Octyldimethyl PABA; Octinoxate (Octyl methoxycinnamate); Octyl salicylate(2-Ethylhexyl Salicylate); Octocrylene (2-cyano-3,3-diphenyl acrylicacid, 2-ethyl hexyl ester); Octyl triazone(2,4,6-Trianalino-(p-Carbo-2′-ethylhexyl-1′oxy) 1,3,5-Triazine);Padimate O (2-Ethylhexyl 4-dimethylaminobenzoate); Phenylbenzimidazolesulfonic acid (2-Phenylbenzimidazole-5-sulfonic acid) and its potassium,sodium and triethanolamine salts;N,N,N-Trimethyl-4-(oxoborn-3-ylidenemethyl) anilinium methylsulfate;Salicylic acid salts (potassium, sodium and triethanolamine); Tinosorb®M(2,2′-Methylene-bis-6-(2H-benzotriazol-2yl)-4-(tetramethyl-butyl)-1,1,3,3-phenol);Titanium dioxide; Triethanolamine salicylate; Zinc oxide; salts orderivatives thereof; and mixtures thereof. Additional suitable sunscreencomponents are described, for example, in International Publication No.WO 2004/071479, and in co-owned, co-pending U.S. patent application Ser.No. 11/187,217, the disclosures of which are hereby incorporated hereinby reference in their entirety for all purposes.

The compositions generally can contain about 1% to about 25% total (w/w)of one or more sun filters. In some embodiments, the foamable suspensiongels will contain about 2%-10%, 4%-8%, 2%-6%, or about 1%, 2%, 3%, 4%,5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13%, 14%, 15%, 20%, or 25% w/wtotal of one or more sun screen components.

In some embodiments, the sun filter is a water dispersable, inert sunfilter, for example, titanium dioxide.

ix. Solvents

In certain optional embodiments, the foamable suspension gels of thepresent subject matter further comprise a volatile solvent, for example,an alcohol. Suitable alcohols include lower alkanols (C₁-C₆ alcohols).Alkanols can be butanol, isobutanol, propanol, isopropanol, ethanol,methanol and mixtures thereof. In certain embodiments, the alkanol isethanol. In one embodiment, the volatile solvent (e.g., alcohol) ispresent in an amount up to 5% w/w, for example, 1%, 2%, 3%, 4%, or 5% ofthe total composition. In certain embodiments, a volatile solvent oralcohol is optional, so that the formulation is non-alcoholic.

x. Propellants

The present foamable suspension gels can contain a propellant. Dependingon the relative densities of the foamable suspension gel base and thepropellant, the propellant can be dispersed within the gel, dissolvedwithin the gel, or layered over or under the gel. Exemplified aerosolpropellants of use include, for example, hydrocarbons,chlorofluorocarbons, dimethyl ether, hydrofluorocarbons, compressedgases, or mixtures thereof.

The maximum amount of propellant used can be determined by itsmiscibility with other components in the composition to form a mixture,such as a homogeneous mixture. The minimal level of propellant used inthe composition can be determined by the desired foam characteristics,and its ability to substantially or completely evacuate the container.

The propellant concentration can be up to about 20%, usually up to about5% or 10%, for example, in the range of about 2-15%, 3-10%, 4-7% w/wrelative to the total amount of composition, for example, about 2%, 3%,4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w/w. In oneembodiment, the amount of propellant added to the foamable suspensiongel compositions is about 2.8 g of propane/butane propellant for eachabout 50 g of the presently described foamable suspension gel bases.

In one embodiment, the propellant is a mixture of propane and butane.The present compositions can be packaged in a polyamide-imide-linedaluminum can and pressurized with a propane/butane mixture as thepropellant. In one embodiment, the propellant can comprise or consist ofa mixture of propane, n-butane, isobutene, and pentane. In oneexemplified embodiment, the propellant can comprise or consist of about55% propane, about 30% n-butane, and about 15% isobutane.

While chlorofluorocarbons (CFCs) can also be used as propellants, due toenvironmental concerns propellants can be hydrocarbons, in particular,propane, butane, pentane, or mixtures thereof. Other suitablepropellants include dimethyl ether, nitrogen, argon, hydrofluorocarbonssuch as 134a and 227, and mixtures of any of the foregoing.

xi. Other Excipients

In some embodiments, the foamable suspension gel comprisespreservatives, emollients, humectants, or other pharmaceuticallyacceptable excipients known in the art.

In addition to those enumerated above, any other dermatologicallyacceptable excipients commonly known to those of ordinary skill in theart as useful in topical compositions are contemplated as useful in thecompositions described herein. Further, any non-toxic, inert, andeffective topical carrier may be used to formulate the compositionsdescribed herein. Well-known carriers used to formulate other topicaltherapeutic compositions for administration to humans will be useful inthese compositions. Examples of these components that are well known tothose of skill in the art are described in The Merck Index, ThirteenthEdition, Budavari et al., Eds., Merck & Co., Inc., Rahway, N.J. (2001);the CTFA (Cosmetic, Toiletry, and Fragrance Association) InternationalCosmetic Ingredient Dictionary and Handbook, Tenth Edition (2004); andthe “Inactive Ingredient Guide”, U.S. Food and Drug Administration (FDA)Center for Drug Evaluation and Research (CDER) Office of Management,January 1996, the contents of which are hereby incorporated by referencein their entirety. Examples of such useful pharmaceutically acceptableexcipients, carriers and diluents include distilled water, physiologicalsaline, Ringer's solution, dextrose solution, Hank's solution, and DMSO,which are among those preferred for use herein.

These additional other inactive components, as well as effectiveformulations and administration procedures, are well known in the artand are described in standard textbooks, such as Goodman and Gillman's:The Pharmacological Bases of Therapeutics, 8th Ed., Gilman et al. Eds.Pergamon Press (1990) and Remington's Pharmaceutical Sciences, 17th Ed.,Mack Publishing Co., Easton, Pa. (1990), both of which are incorporatedby reference herein in their entirety.

b. Physicochemical Properties

i. Viscosity

The foamable suspension gels have an appropriately balanced viscosity,that is sufficiently viscous to hold the one or more active agents in asuspension, but not so viscous so as to be unable to be expelled from acontainer. The suspension gels can have a viscosity that achieves apourable gel and that allows the gel to be expelled easily and evenlyfrom a container. A gel having a viscosity sufficient to maintain theone or more active agents in a suspension also aids in maintaining thechemical and physical stability of the active agents.

In some embodiments, the foamable suspension gels have a final viscosityof less than about 40,000 centipoises (cP), 20,000 cP, 15,000 cP, or10,000 cP at 25° C. In some embodiments, the foamable suspension gel hasa viscosity of about 5,000 cP, 6,000 cP, 7,000 cP, 8,000 cP, 9,000 cP,10,000 cP, 12,000 cP, 15,000 cP, 18,000 cP, 20,000 cP, 25,000 cP, 30,000cP, 35,000 cP, or 40,000 cP at 25° C. In some embodiments, the foamablesuspension gel has a viscosity of about 1,000-20,000 cP, 5,000-15,000cP, 6,000-12,000 cP, or 7,000-10,000 cP at 25° C. In some embodiments,the foamable suspension gel has a viscosity of about 5,000-15,000 at 25°C.

The viscosity of the foamable suspension gels can be measured with asuitable viscosity measuring device. Techniques include: (i) BrookfieldSynchro-lectric rotating spindle viscometer, where the spindle isintroduced into the suspension gel and viscosity is measured at a rangeof temperatures; and (ii) Brookfield Cone & Plate Viscometer, wheresamples of foam are introduced between the cone and plate and therheology of the foam is determined over a range of shear rates andtemperatures.

In a particularly preferred embodiment, the present foamable suspensiongels have a viscosity permitting them to be delivered through anactuator.

ii. Density

The present foamable suspension gels have a density sufficient tomaintain the active agents in a suspension. However, the density can bemore or less than that of the active agents included in the suspensiongel.

In some embodiments, the density at 25° C. of the foamable suspensiongel concentrate is at least about 0.8 g/ml, in the range of about0.8-1.5 g/ml, for example, about 0.8 g/ml, 0.9 g/ml, 0.95 g/ml, 1 g/ml,1.05 g/ml, 1.1 g/ml, 1.15 g/ml, 1.2 g/ml, 1.25 g/ml, 1.3 g/ml, 1.35g/ml, 1.4 g/ml, 1.45 g/ml, or 1.5 g/ml at 25° C.

In contrast, the foam density of the dispensed foam, after dispensingfrom the container, is preferable about 0.6 to about 0.9 g/ml at 25° C.

The density of the present foamable suspension gels can be measured witha suitable density determination apparatus. Techniques include: (i)pycnometer/weight per gallon cup, where the foamable suspension gel atfixed temperatures is carefully introduced into a fixed-volume vessel ofknown volume and mass; and (ii) Electronic density/specific gravitymeter, where a slow stream of foamable suspension gel at fixedtemperatures is introduced into a flow-through cell and the density isdetermined by the oscillating body method.

iii. pH

The pH of the foamable suspension gels will depend on the active agentsincluded in the formulations. The final pH will promote the chemical andphysical stability of the active agents.

In the embodiments where benzoyl peroxide and clindamycin are includedin the foamable suspension gel, the pH is acidic, in the range of about4.0-5.1 or 4.2-4.6 or 4.4-5.1, for example, about 4.00, 4.05, 4.10,4.15, 4.20, 4.25, 4.30, 4.35, 4.40, 4.45, 4.50, 4.55, 4.60, 4.65, 4.70,4.75, 4.80, 4.85, 4.90, 4.95, 5.00, 5.05, or 5.10.

pH values can be measured using techniques known in the art, forexample, by using a pH meter and an appropriate probe.

iv. Particle Size of Active Agents

The particle size of the active agents included in the foamablesuspension gels should be sufficiently small or fine to remain suspendedin the gel and not settle out, to allow for a smooth feel uponadministration of the foamable gel, and to release from the containerwithout clogging the exit channel. The active agent particles should notbe so small so as to become a tightly packed agglomeration that can notbe redispersed upon shaking or so large that they settle out of thefoamable suspension gel or impart a gritty feel to the foam. Theparticles can be of a uniform size or of varying sizes within a range ofdiameters. In one embodiment, greater than about 90% of the active agentparticles are of a uniform size (i.e., monodispersed).

In some embodiments, the particle sizes of the active agents have anaverage diameter of in the range of about 0.5-100 μm, usually less thanabout 20 or 15 μm, more often an average diameter of less about 10 μm,usually in the range of about 5 μm to about 10 μm, for example, with anaverage diameter of about 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 20 μm, or50 μm.

Particle size can be measured using techniques known in the art,including, for example, visual inspection using a microscope (e.g., 100×or 200× magnification).

The extent and rate of settling of particles can be monitored andquantified using techniques known in the art, for example, by subjectingaliquots to a Turbiscan analysis. Equipment for quantifying theturbidity or physical stability of a suspension gel can be purchased,for example, from Formulaction, l'Union (near Toulouse), France.

v. Pressure

The present foamable suspension gels can be packaged in a container. Insome embodiments, the container is pressurized. The pressure in thecontainer should be sufficient to allow the efficient expelling of thefoamable gel. The pressure in the pressurized container should not be sohigh such that the gel releases without control as to application oramount. Also, lower pressures provide for the post-foaming of the gelupon release from the pressurized container.

In some embodiments of the present subject matter, the foamablesuspension gel is in a single container. The container can be apressurized container. In other embodiments, the foamable suspension gelmay be in multiple containers.

In some embodiments, the gel is a post-foaming gel, which foams afterrelease from a container, for example, a pump or pressurized container.

In some embodiments, the container is a non-pressurized container, forexample, a pump, tube, bottle, jar, or any suitable dispensing packageor device.

In some embodiments, the foamable suspension gel comprises an aerosolpropellant. In some embodiments, the container is pressurized, andadditionally contains a propellant. The pressure in the pressurizedcontainer is from about 5 psig to about 110 psig at 21-25° C., forexample, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 100 or 110 psig at 21-25° C.

In some embodiments, the pressurized container is pressurized to about63-80 psig, for example, about 63 psig, 64 psig, 65 psig, 66 psig, 67psig, 68 psig, 69 psig, 70 psig, 71 psig, 72 psig, 73 psig, 74 psig, 75psig, 76 psig, 78 psig, 79 psig, or 80 psig, as measured at 21-25° C.

vi. Stability

As used herein, stability refers to the chemical and physical integrityof the one or more active agents in the foamable suspension gels. One ormore of the active agents may be subject to, for example, oxidation orchemical degradation.

Oxidation of an active agent can be monitored and quantified, forexample, by using a color indicator that changes color in correlation tothe presence or absence of oxidation or the extent of oxidation, forexample, potassium iodide. The potassium iodide is colorless in theabsence of oxidation, turns yellow in the presence of oxidation, andbecomes brown with increasing oxidation. Color changes can be quantifiedusing a spectrophotometer, for example, a ColorQuest Color MeasurementSystem, commercially available from Hunter Associates Laboratory,Reston, Va.

Chemical degradation of an active agent can be monitored and quantified,for example, using high performance liquid chromatography (HPLC).Methods for carrying out HPLC are well known in the art. See, forexample, High Performance Liquid Chromatography: Fundamental Principlesand Practice, Lough, et al., eds., 1996, Kluwer Academic Pub, and Meyer,Practical High-performance Liquid Chromatography, 2004, John Wiley &Sons. Degradation can be quantified by measuring the decrease of peaksize (e.g., height of a peak or area under a peak) on the data output ofpeaks indicating undegraded active agent (e.g., benzoyl peroxide orclindamycin), and/or the increase of peak size of peaks indicatingdegraded active agent (e.g., benzoic acid or clindamycin sulfoxideisomers).

Stability can depend on time and temperature. Preferably, at least about90%, 93%, 95%, or 97% of undegraded active agent is detected in thesuspension gel formulation after at least about 3, 4, 5, 6 months at 5°C., 25° C. or 30° C. For example, the foamable suspension gels canretain at least about 80%, 85%, 90% undegraded active agent for at least6 months at 25° C. The foamable suspension gels can retain at leastabout 90%, 95%, 96%, 97%, 98% undegraded active agent for at least 12months, or at least 24 months at 5° C. The amount of undegraded activeagent can be measured in comparison to the freshly prepared gel or incomparison to the amount of degraded active agent formed.

In some embodiments, the first and second active agents within thefoamable suspension gel are chemically and physically stable for atleast 3 months, 4 months, 5 months, 6 months at 5° C., 25° C. or 30° C.In some embodiments, the first and second active agents within thefoamable suspension gel are chemically and physically stable for atleast 12 months, or for at least 24 months, at 5° C.

Methods of Treating a Dermatological Condition

The present subject matter also provides for methods of therapeuticallyand prophylactically treating a dermatological condition by topicallyapplying the foam of the foamable suspension gels of the present subjectmatter to affected areas. Exemplified dermatological conditions suitablefor treatment by the present foamable suspension gels include rashes,eczema, contact dermatitis, acne (including acne vulgaris and acnerosacea), fungal infections, and bacterial infections. The foamablesuspension gels are particularly suitable for treating acne.

Acne is treated both therapeutically and prophylactically by applyingthe foam of the foamable suspension gel to the skin in areas where acnelesions are present or likely to be present. The foam is generallyrubbed into the skin until the foam is totally collapsed. The foam canbe applied one, two, three, four or more times a day, as needed, or asdirected by a healthcare provider. The collapsed foam may be left on theskin or washed off as desired depending upon the purpose of application.Alternatively, the foam may be applied as a facial mask and washed offafter use.

Combination Therapy

In another preferred embodiment, the present preferred compositions maybe used in combination with an additional pharmaceutical dosage form toenhance their effectiveness in treating a dermatological disease ordisorder, particularly acne. In this regard, the present preferredcompositions may be administered as part of a regimen additionallyincluding any other pharmaceutical and/or pharmaceutical dosage formknown in the art as effective for the treatment of a dermatologicaldisorder. Similarly, a pharmaceutically active ingredient other thanthose specified herein can be added to the present preferredcompositions to enhance their effectiveness in treating a dermatologicaldisease or disorder. Accordingly, this additional pharmaceuticallyactive ingredient or additional pharmaceutical dosage form can beapplied to a patient either directly or indirectly, and concomitantly orsequentially, with the preferred compositions described herein.

In one embodiment in this regard, the present preferred composition andthe additional pharmaceutical dosage form can be administered to apatient at the same time. In an alternative embodiment, one of thepresent preferred compositions and the additional pharmaceutical dosageform can be administered in the morning and the other can beadministered in the evening.

Methods of Producing a Foamable Suspension Gel

The manufacturing process for the present foamable suspension gel baseinvolves the preparation of several phases that are subsequentlycombined. This is largely due to the particulate nature of the firstactive agent that is sparingly soluble to insoluble in water.

In one approach, a “gel concentrate” is prepared by combining water anda thickening agent. Thereafter, the first active agent is mixed with adispersing/wetting agent to form a homogenous dispersion while mixing.Mixing of the dispersion containing the first active agent is continuedto prevent the first active agent from settling to the base of themixing vessel and creating a solid “cake.”

Next, the gel concentrate is admixed to the dispersion containing thefirst active agent during stirring to produce a physically stable gelholding the first active agent in suspension. The size of particles ofthe first active agent (and other active agents) in the gel can bereduced through a milling process.

Where the suspension gel is intended to include one or more secondactive agents, the following subsequent steps are undertaken. In aseparate vessel, a gel containing a thickening agent and the secondactive agent is prepared. When the second active agent is a lincomycinantibiotic, such as clindamycin phosphate, no pH adjustment isnecessary. That is, the pH of the solution containing clindamycinphosphate is below pH 5.5, below pH 5.2 or below pH 5, such as pH 4 to4.5 (e.g., 4, 4.1, 4.2, 4.3, 4.4, or 4.5).

Subsequently, the gel containing the first active agent is blended witha gel containing the second active agent, resulting in a foamablesuspension gel base containing the first and second active agents (andother active agents).

The foamable suspension gel base can then be added into the individualcontainers during the filling operation. The valves are fitted to thecans and crimped into place. In pressurized containers, a metered amountof propellant can be injected through the valve to complete theformulation. Another means of filling the cans involves asingle-liquid-phase fill, in which the composition is kept warm toensure homogeneity, followed by crimping and propellant injection. Yetanother means involves formulating the entire composition, including thepropellant, in bulk, under pressure, and then injecting the formulationinto a crimped aerosol can.

The compositions made according to this method are preferably in anaerosol dosage form suitable for topical application. Accordingly, saidproduction method can additionally comprise the further step of chargingthe container with a propellant suitable to effect aerosol delivery ofthe composition from the container.

The effectiveness of the present pharmaceutical formulations depends onachieving the proper combination of formulation, container, and valveassembly.

The Container

The instant foamable pharmaceutical compositions are preferably packagedin a container as an aerosol. The compositions may be packaged in thecontainer using either a single-step or a multiple-step filling processcommonly known to those of ordinary skill in the art.

The container must be selected to provide the aerosol formulation with along shelf life. Accordingly, the container must be chemically inertwith respect to the composition contained therein so as not to interferewith the stability of the formulation or with the integrity andoperation of the container. Further, the container must be capable ofwithstanding the pressure required by the product, must becorrosive-resistant, and must be resistant to physical or chemicalchanges to the product contained therein that may, for example, formparticles clogging the orifice. This is particularly important as thepresent compositions contain a surfactant and an acid, two componentsknown to increase the potential for corrosion.

The selection of a suitable container for the aerosol product is basedon its adaptability to production methods, compatibility withformulation components, ability to sustain the pressure intended for theproduct, the interest in design and aesthetic appeal on the part of themanufacturer, and cost. Suitable containers may be made of, for example,steel, aluminum, glass, plastic, or mixtures thereof. The containers mayfurther employ one or more protective coatings such as, for example,sodium nitrate, sodium benzoate, ammonium m-nitrobenzoate, morpholine,2-methyl butynoyl, Expoxol 9-5, sodium n-lauroylsarcosinate, phenolic,epoxy, or vinyl coatings, to enhance the formulation compatibility orsafe handling. Any other known aerosol containers and protectivecoatings are further contemplated as useful in this regard.

The container may also comprise two or more compartments permitting thefinal composition to be broken up into separate portions that arephysically separated until dispensed from the container through thevalve assembly.

Known methods for filling aerosol containers with foamable compositionsinclude processes known as cold fill, under the cup, and pressure fill(through the valve). Such methods for filling an aerosol container arewell known to those of ordinary skill in the art and may be found in TheAerosol Handbook (Wayne E. Dorland, Caldwell, N.J.) and the Handbook ofAerosol Technology, (R. E. Krieger, Malabar, Fla.), both of which areincorporated by reference in their entirety.

In the cold filling method, both the product concentrate and thepropellant must be cooled to temperatures of −30° to −40° F. The chilledproduct concentrate is quantitatively metered into an equally coldaerosol container, then the cold, liquefied gas is added. Whensufficient propellant has been added, the valve assembly is placed onthe container.

In the under the cap filling method, a filling head that forms a tightseal on the container shoulder is utilized. The filling head holds thevalve above the container while propellant under pressure is addedthrough the opening in the container.

In the pressure filling method, the product concentrate isquantitatively placed in the container, the valve assembly is placed onthe container, and the liquefied gas, under pressure, is metered throughthe valve stem into the container. Pressure filling is used for mostpharmaceutical aerosols.

Valve Assembly

The function of the valve assembly is to permit the expulsion of thecontents of the can in the desired form, at the desired rate, and, inthe case of metered valves, in the proper amount or dose. Accordingly,the valve assembly must contribute to the form of the product to beemitted. In particular, aerosol foam valves typically have alarge-diameter delivery spout to permit the delivery of the foam.Further, the valve assembly permits the aerosol composition to bereleased from the container either via continuous delivery or as ametered dose.

The materials used in the manufacture of the valve assembly must beinert towards the aerosol formulations that pass therethrough. Among thematerials that can be used in the manufacture of the various valve partsare plastic, rubber, aluminum, stainless steel, and mixtures thereof.The usual aerosol valve assembly is composed of the following parts:actuator, stem, gasket, spring, mounting cup, housing, and dip tube.Valves may also be employed that permit emission of product while thecontainer is upright or inverted. All types of valve assemblies known tothose of ordinary skill in the art, including spray valves, slidinggasket valves, deflecting gasket valves, and tilt action valves, arecontemplated as capable of delivering the present inventivecompositions.

Metering valves are designed to deliver specific quantities of a producteach time the valve is actuated. Meter valves are usually employed whenthe formulation is a potent medication or in other instances where aprecise dosing is desired. In metered valve systems, an auxiliary valvechamber regulates the amount of material discharged by virtue of itscapacity or dimensions.

The valve assembly may further accommodate an attachment to facilitatedelivery of the present inventive foamable pharmaceutical compositions.

Dosage

Appropriate dosage levels for any of the herein described activeingredients are well known to those of ordinary skill in the art and areselected to maximize the treatment of the previously described microbialand/or fungal conditions. Dosage levels on the order of about 0.001 mgto about 5,000 mg per kilogram body weight of the active ingredientcomponents are known to be useful in the treatment of the diseases,disorders, and conditions contemplated herein. Typically, this effectiveamount of the active agent will generally comprise from about 0.001 mgto about 100 mg per kilogram of patient body weight per day. Moreover,it will be understood that this dosage of ingredients can beadministered in a single or multiple dosage units to provide the desiredtherapeutic effect.

If desired, other therapeutic agents can be employed in conjunction withthose provided in the above-described compositions. The amount ofpharmaceutically active ingredients that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the nature of the disease, disorder, orcondition, and the nature of the active ingredients.

The preferred pharmaceutical compositions may be given in a single ormultiple doses daily. In a preferred embodiment, the pharmaceuticalcompositions are given from one to three times daily. Starting with alow dose twice daily and slowly working up to higher doses if needed isa preferred strategy. The amount of pharmaceutically active ingredientsthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated, the nature of thedisease, disorder, or condition, and the nature of the activeingredients.

It is understood, however, that a specific dose level for any particularpatient will vary depending upon a variety of factors, including theactivity of the specific pharmaceutically active agent; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration; the rate of excretion; possible drug combinations; theseverity of the particular condition being treated; and the form ofadministration. One of ordinary skill in the art would appreciate thevariability of such factors and would be able to establish specific doselevels using no more than routine experimentation.

The optimal pharmaceutical formulations will be determined by oneskilled in the art depending upon considerations such as the particularpharmaceutically active agent combination and the desired dosage. See,for example, “Remington's Pharmaceutical Sciences”, 18th ed. (1990, MackPublishing Co., Easton, Pa. 18042), pp. 1435-1712, the disclosure ofwhich is hereby incorporated by reference. Such formulations mayinfluence the physical state, stability, rate of in vivo release, andrate of in vivo clearance of the essential lipids.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed subject matter.

Example 1 Exemplified Foamable Suspension Gel Containing BenzoylPeroxide and Clindamycin

This example demonstrates the manufacture of one embodiment of thefoamable suspension gels, containing benzoyl peroxide and clindamycin.

Components

Ingredient Item # Name Grade Trade Name Manufacturer/Vendor % w/wBenzoyl Peroxide Dispersion 1 Purified Water USP Purified Water — 4.3302 Poloxamer 188 USP Lutrol ® F68 BASF 1.000 3 Anhydrous USP Citric acidMerck 0.150 Citric Acid anhydrous powder EMPROVE ® 4 Sodium Citrate USPTri-Sodium citrate Merck 0.350 dihydrate dihydrate cryst. EMPROVE ® 5Hydrous USP Luperox ® A75FP/ Arkema (Atofina) 6.670 Benzoyl BenzoylPeroxide, Chemical/Sigma - Peroxide 75% USP Aldrich Remainder WaterSub-total (Items 1-5) 12.500 2% Xanthan Gum 6 Purified Water USPPurified Water — 36.675 7 Edetate USP Dissolvine ®, NA2-P Akzo Nobel0.075 Disodium 8 Xanthan Gum USP Xantural ® 11K CP Kelco 0.750 Sub-total(Items 6-8) 37.500 Clindamycin Phosphate Gel 9 Purified Water USPPurified Water — 48.475 10 Clindamycin USP Clindamycin AbbottLaboratories 1.250 Phosphate Phosphate, USP 11 Xanthan Gum USPXantural ® 11K CP Kelco 0.250 12 Edetate USP Dissolvine ®, NA2-P AkzoNobel 0.025 Disodium Sub-total (Items 9-12) 50.000 Total 100.00

Final concentrations of components in gel base:

Ingredients Example 1 Purified water 89.48% Citric Acid 0.12-0.20%tri-Sodium Citrate 0.30-0.38% Disodium EDTA 0.10% Poloxamer 188 1.00%Clindamycin 1.25% Phosphate Benzoyl Peroxide 6.67% Xanthan Gum 1.00% pHat room 4.0-5.5 temperature

Example 2 Exemplified Foamable Suspension Gel Bases Containing BenzoylPeroxide and Clindamycin

Example Ingredients Example 2A Example 2B Example 2C 2D Purified water89.48% 89.48% 89.48% 89.48% Citric Acid 0.12% 0.15% 0.18% 0.20%tri-Sodium Citrate 0.38% 0.35% 0.32% 0.30% Disodium EDTA 0.10% 0.10%0.10% 0.10% Poloxamer 188 1.00% 1.00% 1.00% 1.00% Clindamycin 1.25%1.25% 1.25% 1.25% Phosphate Benzoyl Peroxide 6.67% 6.67% 6.67% 6.67%Xanthan Gum 1.00% 1.00% 1.00% 1.00% pH at room 4.5-5.5 4.5-5.5 4.0-5.04.0-5.0 temperature

Example 3 Exemplified Foamable Suspension Gel Bases Containing BenzoylPeroxide and Clindamycin and a Sun Filter

Ingredients Example 3A Example 3B Example 3C Purified water 85.48%87.48% 84.48% Citric Acid 0.12-0.20% 0.12-0.20% 0.12-0.20% tri-SodiumCitrate 0.30-0.38% 0.30-0.38% 0.30-0.38% Disodium EDTA 0.10% 0.10% 0.10%Poloxamer 188 1.00% 1.00% 1.00% Clindamycin 1.25% 1.25% 1.25% PhosphateBenzoyl Peroxide 6.67% 6.67% 6.67% Xanthan Gum 1.00% 1.00% 1.00%Sunscreen Grade 4.00 — — TiO₂ (UV absorber) PEG-25 PABA (UV — 2.00 —absorber) Tinosorb ® M (UV — — 5.00 absorber) pH at room 4.0-5.5 4.0-5.54.0-5.5 temperature

The UV absorbing ingredients in Examples 3A, 3B and 3C are the lastingredients added to the foamable suspension gel. The foamablesuspension gels containing one or more sun filters are blended until theUV absorbers are uniformly dispersed throughout the gel.

Example 4 Exemplified Foamable Suspension Gel Bases Containing BenzoylPeroxide and Clindamycin and a Retinoid

Ingredients Example 4A Example 4B Example 4C Purified water 89.455%89.38% 89.43% Citric Acid 0.12-0.20% 0.12-0.20% 0.12-0.20% tri-SodiumCitrate 0.30-0.38% 0.30-0.38% 0.30-0.38% Disodium EDTA 0.10% 0.10% 0.10%Poloxamer 188 1.00% 1.00% 1.00% Clindamycin 1.25% 1.25% 1.25% PhosphateBenzoyl Peroxide 6.67% 6.67% 6.67% Xanthan Gum 1.00% 1.00% 1.00%Tretinoin (Retinoid) 0.025 0.10 0.05 pH at room 4.0-5.5 4.0-5.5 4.0-5.5temperature

The retinoid in Examples 4A, 4B and 4C is the last ingredient added tothe foamable suspension gel. The final concentration of retinoid can bebetween about 0.025% to about 0.10% w/w. The foamable suspension geladditionally containing one or more retinoids as a third active agentare blended until the retinoid is uniformly dispersed throughout thegel.

Examples 5-9 Exemplified Foamable Suspension Gel Bases ContainingBenzoyl Peroxide; Benzoyl Peroxide and Sodium Sulfacetamide;Metronidazole and Sodium Sulfacetamide; and Azole Antimicrobial Agentand Salicylic Acid

Example Number: 6 8a 8b 9 5 2.5% Benzoyl 7 0.75% 1% 2% 10% Peroxide/ 5%Sulfur/ Metronidazole/ Clotrimazole/ Miconazole Benzoyl 10% Sodium 10%Sodium 10% Sodium 10% Sodium Nitrate/2% Peroxide SulfacetamideSulfacetamide Sulfacetamide Sulfacetamide Salicylic Foam Foam Foam FoamFoam Acid Foam % w/w % w/w % w/w % w/w % w/w % w/w Ingredient Water,purified 84.17 62.4 82.4 86.65 85.40 93.4 EDTA, Disodium 0.50 0.10 0.100.10 0.10 0.10 Sodium 0 0.5 0.5 0.5 0.5 0 Phosphate, dibasic/SodiumPhosphate, monobasic Citric 0 0 0 0 0 0.5 Acid/Potassium CitratePoloxamer 188 1.00 1.00 1.00 1.00 1.00 1.00 Salicylic Acid 0 0 0 0 02.00 Sulfur 0 0 5.00 0 0 0 Miconazole 0 0 0 0 2.00 2.00 NitrateMetronidazole 0 0 0 0.75 0 0 Sodium 0 10.00 10.00 10.00 10.00 0Sulfacetamide Benzoyl Peroxide 0 25.00 0 0 0 0 (10%) EncapsulatedBenzoyl Peroxide 13.33 0 0 0 0 0 (75%) Xanthan Gum 1.00 1.00 1.00 1.001.00 1.00 Aerosol Base 100.00 100.00 100.00 100.00 100.00 100.00 TotalpH @ 25° C. 4 to 5 6.8 to 7.5 6.8 to 7.5 6.8 to 7.5 6.5 to 7.5 5 to 6.5Filling Details: Aerosol Base 95.00 95.00 95.00 95.00 95.00 95.00(Above) Hydrocarbon 5.00 5.00 5.00 5.00 5.00 5.00 Propellant 100.00100.00 100.00 100.00 100.00 100.00

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. An aqueous foamable suspension gel in apressurized container, comprising: an aqueous phase comprising water;from about 1% to about 8% w/w based on the total weight of the gel ofbenzoyl peroxide suspended in the aqueous phase; from about 0.025% toabout 2% w/w based on the total weight of the gel of a retinoid; athickening agent in an amount sufficient to result in a foamablesuspension gel having a viscosity of about 1,000 to about 20,000centipoise at 25° C.; and an aerosol propellant; wherein the gel isoil-free and alcohol-free and forms a homogenous foam when dispensedfrom the pressurized container.
 2. The foamable suspension gel of claim1, wherein the gel comprises at least 70% w/w water, based on the totalweight of the gel.
 3. The foamable suspension gel of claim 1, furthercomprising a surfactant.
 4. The foamable suspension gel of claim 1,further comprising a wetting agent.
 5. The foamable suspension gel ofclaim 1, further comprising a sun filter.
 6. The foamable suspension gelof claim 1, wherein the gel has a viscosity of about 5,000 centipoise(cP) to about 15,000 cP at 25° C.
 7. The foamable suspension gel ofclaim 1, wherein the gel is a post-foaming gel that foams after releasefrom the container.
 8. The foamable suspension gel of claim 1, whereinthe thickening agent is a hydrocolloid.
 9. The foamable suspension gelof claim 8, wherein the thickening agent is selected from the groupconsisting of xanthan gum, a carbomer, salts or derivatives thereof, andmixtures thereof.
 10. The foamable suspension gel of claim 1, whereinthe pressure in the pressurized container is from about 5 psi to about110 psi at 25° C.
 11. The foamable suspension gel of claim 1, furthercomprising a pH-adjusting agent.
 12. The foamable suspension gel ofclaim 1, wherein the pH of the foam is about 4-9.
 13. An aqueousfoamable suspension gel in a pressurized container, comprising: anaqueous phase comprising water; from about 1% to about 8% w/w based onthe total weight of the gel of benzoyl peroxide suspended in the aqueousphase; from about 0.025% to about 2% w/w based on the total weight ofthe gel of a retinoid; one or more thickening agents; and an aerosolpropellant; wherein the gel is oil-free and alcohol-free, has aviscosity of about 5,000 to about 15,000 centipoise (cP) at 25° C., andforms a homogenous foam when dispensed from the pressurized container.14. A method of treating acne, the method comprising contacting the skinof an individual in need thereof with the foamable suspension gel ofclaim
 13. 15. An aqueous foamable suspension gel in a pressurizedcontainer, comprising: an aqueous phase comprising water; from about 1%to about 8% w/w based on the total weight of the gel benzoyl peroxidesuspended in the aqueous phase; from about 0.025% to about 2% w/w basedon the total weight of the gel of a retinoid; one or more thickeningagents; optionally one or more excipients selected from the groupconsisting of a dispersing/wetting agent, a pH-adjusting, a surfactant,a sunfilter, an antioxidant, an additional foaming agent, achelating/sequestering agent, a coloring agent and a preservative; andan aerosol propellant; wherein the gel is oil-free and alcohol-free, hasa viscosity of about 5,000 to about 15,000 centipoise (cP) at 25° C.,and forms a homogenous foam when dispensed from the pressurizedcontainer.
 16. A method of treating acne, the method comprisingcontacting the skin of an individual in need thereof with the foamablesuspension gel of claim
 1. 17. The foamable suspension gel of claim 1,wherein the aerosol propellant is selected from the group consisting ofa hydrocarbon, a chlorofluorocarbon, dimethyl ether, a hydrofluorocarbonand a compressed gas, and mixtures thereof.
 18. The foamable suspensiongel of claim 17, wherein the aerosol propellant is a hydrocarbon. 19.The foamable suspension gel of claim 1, wherein the aerosol propellantis present in an amount from about 3% to about 10% by weight, based onthe total weight of the gel.